Nicotine composition for vaping devices and vaping devices employing the same

ABSTRACT

A composition suitable for use in a vaping device includes a nicotine product that includes a synthetic nicotine that is substantially free of one or more contaminants and/or impurities normally associated with tobacco-derived nicotine. For example, the synthetic nicotine is substantially free of one or more of nicotine-1′-N-oxide, nicotyrine, nornicotyrine, 2′,3-bipyridyl, cotinine, anabasine, and/or anatabine. The composition further comprises one or more pharmaceutically acceptable excipients, additives and/or solvents.

CROSS REFERENCE TO RELATED APPLICATION

This application claims priority to and the benefit of U.S. Provisional Application Ser. No. 62/245,795, filed on Oct. 23, 2015 and titled “(R,S)-NICOTINE AND METHOD OF USE THEREOF,” the entire content of which is incorporated herein by reference.

BACKGROUND

Compositions currently used in electronic vaping devices, also referred to herein as “vaporization devices” or “vaping devices,” generally include nicotine in diluted liquid form. The nicotine used in such compositions is a derived, purified extract of tobacco leaves. These extracts are isolated in semi-pure form along with many contaminants, many of which have been shown to cause serious ailments for the human system, including cancer. For example, tobacco-derived nicotine when purified to levels compliant with the United States Pharmacopeia (USP) monograph for purity still has many contaminants, and these contaminants have a high potential to be problematic for the consumer because many are known carcinogens and agents of addiction. Additionally, these contaminants contribute to the characteristic foul taste and foul smell of commercially available products utilizing tobacco-derived nicotine extracts. Significantly, vaping products having tobacco-derived nicotine often require relatively large amounts of flavorants, as well as other additional masking chemicals, which are added to the composition to mask the foul taste and/or smell of the tobacco-derived nicotine. These masking chemicals and the large amount of flavorants required to mask the foul taste affect the taste and experience of vaping, and may themselves have a detrimental impact to the user.

SUMMARY

According to aspects of embodiments of the present invention, a composition suitable for vaporizing, comprises a nicotine product comprising a synthetic nicotine that is free or substantially free of certain contaminants or impurities normally present in tobacco-derived nicotine, such as, for example nicotine-N′-oxide (e.g., nicotine-1′-N-oxide), nicotyrine (e.g., β-Nicotyrine), cotinine, nornicotyrine, 2′,3-bipyridyl, anabasine, and/or anatabine. In some embodiments, the composition may further include one or more pharmaceutically acceptable carriers, additives and/or excipients.

Additional advantages and novel features of various aspects of embodiments the present invention will be set forth in part in the description that follows, and in part will become more apparent to those skilled in the art upon examination of the following or upon learning by practice thereof.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a schematic representation of a prior art electronic vaping device useable for vaporizing a nicotine composition in accordance with aspects of embodiments of the present invention.

DETAILED DESCRIPTION

The following description of certain example embodiments of the invention should not be used to limit the scope of the present invention. Other examples, features, aspects, embodiments, advantages, and one of the best modes contemplated for carrying out the invention will become apparent to those skilled in the art from the following description, which is provided for illustration only, and is in no way designed to limit the scope of the present invention. As will be realized, various different modifications may be made to the described embodiments of the present invention without departing from the scope of the present invention. Accordingly, the drawings and descriptions should be regarded as illustrative in nature and not restrictive.

According to aspects of embodiments of the present invention, a composition suitable for vaporizing (also referred to herein as a “vaping composition” or “vaping solution”) comprises a nicotine product comprising a synthetic nicotine that is free or substantially free of certain contaminants or impurities normally found in tobacco-derived nicotine, such as, for example nicotine-N′-oxide (e.g., nicotine-1′-N-oxide), nicotyrine (e.g., β-Nicotyrine), cotinine, nornicotyrine, 2′,3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine. In some embodiments, for example, the composition may include a synthetic nicotine that is free or substantially free of any one or more of nicotine-N′-oxide (e.g., nicotine-1′-N-oxide), nicotyrine (e.g., β-Nicotyrine), cotinine, nornicotyrine, 2′,3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine. In some embodiments, the composition may include a synthetic nicotine that is free or substantially free of any combination of two or more of nicotine-N′-oxide (e.g., nicotine-1′-N-oxide), nicotyrine (e.g., β-Nicotyrine), cotinine, nornicotyrine, 2′,3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine. In some embodiments, the composition may include a synthetic nicotine that is free or substantially free of all of nicotine-N′-oxide (e.g., nicotine-1′-N-oxide), nicotyrine (e.g., β-Nicotyrine), cotinine, nornicotyrine, 2′,3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.

According to aspects of embodiments of the present invention, a composition suitable for vaporizing (also referred to herein as a “vaping composition” or “vaping solution”) comprises a nicotine product comprising a synthetic nicotine that is free or substantially free of nicotyrine (e.g., β-Nicotyrine), cotinine, nornicotyrine, 2′,3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine. In some embodiments, for example, the composition may include a synthetic nicotine that is free or substantially free of any one or more of nicotyrine (e.g., β-Nicotyrine), cotinine, nornicotyrine, 2′,3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine. In some embodiments, the composition may include a synthetic nicotine that is free or substantially free of any combination of two or more of nicotyrine (e.g., β-Nicotyrine), cotinine, nornicotyrine, 2′,3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine. In some embodiments, the composition may include a synthetic nicotine that is free or substantially free of all of nicotyrine (e.g., β-Nicotyrine), cotinine, nornicotyrine, 2′,3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.

For example, in some embodiments, a vaping composition or vaping solution comprises a nicotine product comprising a synthetic nicotine that is free or substantially free of nicotyrine (e.g., β-Nicotyrine), cotinine, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine. In some embodiments, for example, the composition may include a synthetic nicotine that is free or substantially free of any one or more of nicotyrine (e.g., β-Nicotyrine), cotinine, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine. In some embodiments, the composition may include a synthetic nicotine that is free or substantially free of any combination of two or more of nicotyrine (e.g., β-Nicotyrine), cotinine, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine. In some embodiments, the composition may include a synthetic nicotine that is free or substantially free of all of nicotyrine (e.g., β-Nicotyrine), cotinine, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine.

In some embodiments, for example, a vaping composition or vaping solution comprises a nicotine product comprising a synthetic nicotine that is free or substantially free of anabasine, N-methyl anatabine, N-methyl anabasine, cotinine and/or anatabine. In some embodiments, for example, the composition may include a synthetic nicotine that is free or substantially free of one or more of anabasine, N-methyl anatabine, N-methyl anabasine, cotinine, and/or anatabine. In some embodiments, the composition may include a synthetic nicotine that is free or substantially free of two or more of anabasine, N-methyl anatabine, N-methyl anabasine, cotinine and/or anatabine. For example, in some embodiments, the composition may include a synthetic nicotine that is free or substantially free of two or more of anabasine, N-methyl anatabine, N-methyl anabasine, cotinine and/or anatabine.

Those of ordinary skill in the art would understand known methods of determining the presence of the compounds and impurities discussed herein. However, one nonlimiting example of a suitable technique for determining whether these impurities are present in a particular composition includes USP-HPLC, i.e., high performance liquid chromatography according to USP standards, which tests for the main impurities in tobacco-derived or natural nicotine (including, e.g., cotinine and anatabine). Those of ordinary skill in the art would be readily capable of performing such a technique, and would recognized a yield of a detectable amount of any of the impurities or contaminants found in tobacco-derived nicotine confirms the composition as natural or tobacco-derived nicotine.

The synthetic nicotine according to embodiments of the present invention is distinct and distinguishable from its tobacco-derived or natural counterpart. In particular, as discussed further in the Examples section herein, the synthetic nicotine according to embodiments of the present invention provides an improved overall “vaping” experience that maintains a satisfactorily strong head feel dynamic while also reducing the unpleasant throat feel associated with the “vaping” of tobacco-derived or natural nicotine. The impurities discussed above are one way in which the synthetic nicotine according to embodiments of the present invention may be chemically and physically distinguished from tobacco-derived or natural nicotine. However, additional methods for distinguishing synthetic vs. natural nicotine may also be used. For example, because natural nicotine is derived from, or extracted from a living tobacco plant, the nicotine obtained from that source will inherently include a measurable amount of radioactive isotopes, e.g., ¹⁴C, ¹³C and D. See Randolph A. Culp et al., “Identification of Isotopically Manipulated Cinnamic Aldehyde and Benzaldehyde,” J. Agric. Food Chem., 1990, 38, 1249-1255; and Randolph A. Culp et al., “Determination of Synthetic Components in Flavors by Deuterium/Hydrogen Isotopic Ratios,” referred to collectively herein as “the Culp references”, the entire contents of both of which are incorporated herein by reference. As noted in the Culp references, a natural (or plant-derived) source of a compound can be determined through isotopic analysis to determine the level of ¹⁴C as well as the isotopic abundance of ¹³C and D (typically reported as δ¹³C and δD, respectively). The δ¹³C and δD indications refer to the isotopic abundance, i.e., the ratio of the heavier isotope (e.g., ¹³C or D) to the lighter isotope (e.g., ¹²C or H). As discussed in the Culp references, these ratios are measurably different in corresponding synthetic vs. naturally-derived or plant-derived compounds. As such, in some embodiments of the present invention, the synthetic nicotine has an isotopic abundance (e.g., a δ¹³C and δD value) and/or ¹⁴C level that is different from that of the natural or tobacco-derived counterpart compound. For example, in some embodiments, the synthetic nicotine has an isotopic abundance (e.g., a δ¹³C and δD value) and/or ¹⁴C level that is lower than that of the natural or tobacco-derived counterpart compound. For example, in some embodiments, the synthetic nicotine may have a ¹⁴C level of up to about 10 dpm/gC (distintegrations per minute/grams C). In some embodiments, for example the synthetic nicotine may have ¹⁴C level of about 0.1 to about 9 dpm/gC, or in some embodiments about 2 to about 8 dpm/gC, or about 3 to about 8 dpm/gC. For example, in some embodiments, the synthetic nicotine may have a ¹⁴C level of about 3.5 to about 7 dpm/gC, or about 4 to about 6 dpm/gC. In contrast, the 2015 and day ¹⁴C reference standard is 14.0 dpm/gC. Accordingly, the synthetic nicotine according to embodiments of the present invention has a significantly different ¹⁴C level than that of natural nicotine (i.e., based on the 2015 and present day reference standard for ¹⁴C activity). For example, in some embodiments the synthetic nicotine has a ¹⁴C level that is up to about 72% that of natural nicotine, or about 0.5% to about 65% that of natural nicotine. In some embodiments, for example, the synthetic nicotine has a ¹⁴C level that is about 14% to about 58% that of natural nicotine, or about 20% to about 58% that of natural nicotine. For example, in some embodiments, the synthetic nicotine has a ¹⁴C level that is about 25% to about 50% that of natural nicotine, or about 28% to about 43% that of natural nicotine.

As referenced above, the unstable radio-isotope of carbon, ¹⁴C, has different radioactivity based on its age, e.g., the older it is, the less radioactive it becomes. Comparison of the radioactivity of natural or tobacco-derived nicotine (e.g., the United States Phamacopeia (USP)) standard to that of a synthetic sample provides an avenue for identifying the source of the nicotine. For example, if the nicotine is petroleum based, then the radioactivity will be significantly lower than if the nicotine is natural or tobacco-derived. However, some synthetic nicotine may be produced from chemicals that originate from living plants, e.g., sugar cane or corn. To tell the difference between tobacco-derived nicotine and such sugar- or corn-derived nicotine, the amounts of the stable isotope of carbon is determined. Since sugar cane and corn are in a different class of plant than tobacco, they metabolize the heavy isotopes of carbon (C¹³) and water (D₂O) at different magnitudes than the tobacco plant. As such, if the comparative measurement data for these stable isotopes is different, then it can be determined that the nicotine is not from tobacco; and if the comparative measurement data is similar, then it can be determined that the nicotine is from tobacco. For example, natural nicotine has a δ¹³C (¹³C/¹²C) around ˜30 to −32 parts per mil relative to the international standard PDB (±σ). In contrast, according to embodiments of the present invention, the synthetic nicotine may have a δ¹³C of about −20 to about −29 parts per mil relative to the international standard PDB (±σ), or about −23 to about −29 parts per mil relative to the international standard PDB (±σ). In some embodiments, for example, the synthetic nicotine may have a δ¹³C of about −25 to about −28.5 parts per mil relative to the international standard PDB (±σ), or about −26 to about −28.5 parts per mil relative to the international standard PDB (±σ). As such, the synthetic nicotine according to embodiments of the present invention may have a δ¹³C that is about 66% to about 97% that of natural nicotine, or about 76% to about 97% that of nicotine. For example, in some embodiments, the synthetic nicotine according to embodiments of the present invention may have a δ¹³C that is about 83% to about 95% that of natural nicotine, or about 87% to about 95% that of nicotine.

Additionally, natural nicotine has a δD (D/H) around −170 to −171 parts per mil relative to the international standard V-SMOW (±σ). In contrast, according to embodiments of the present invention, the synthetic nicotine may have a δD of about −140 to about −160 parts per mil relative to the international standard V-SMOW (±σ), or about −145 to about −160 parts per mil relative to the international V-SMOW (±σ). In some embodiments, for example, the synthetic nicotine may have a δD of about −150 to about −160 parts per mil relative to the international standard V-SMOW (±σ), or about −152 to about −158 parts per mil relative to the international standard V-SMOW (±σ). As such, the synthetic nicotine according to embodiments of the present invention may have a δD that is about 82% to about 95% that of natural nicotine, or about 85% to about 95% that of nicotine. For example, in some embodiments, the synthetic nicotine according to embodiments of the present invention may have a δD that is about 88% to about 95% that of natural nicotine, or about 89% to about 93% that of nicotine.

The compositions may further include one or more pharmaceutically acceptable excipients, additives and/or carriers. As used herein, the term “substantially” is used as a term of approximation, and not as a term of degree, and is intended to account for the possibility of incidental impurities in the listed component. For example, the term “substantially free of the listed compounds refers to a composition that does not include added amounts of the listed compounds, and refers to the inclusion of any such components in the composition only as incidental impurities in negligible amounts that do not contribute to the function or properties of the composition. In contrast, a composition that is” free of or “completely free of” the listed compounds contains no measurable amount of the listed components.

In aspects of embodiments of the present invention, the composition for use in an electronic vaping device may comprise nicotine. The composition may be a solid or liquid mixture, for example liquid, and may comprise about 0.001 wt % to about 0.50 wt %, for example about 0.1 wt % to about 0.40 wt %, or about 0.2 wt % to about 0.35 wt % nicotine based on the total weight of the composition. In some embodiments, the composition may comprise about 0.3 wt % nicotine. On a weight per volume basis, the composition may comprise about 0.1 mg/ml to about 50 mg/ml, for example about 1 mg/ml to about 40 mg/ml, or about 2 mg/ml to about 35 mg/ml of the nicotine, based on the total volume of the composition. For example, in some embodiments, the composition may comprise about 30 mg/ml of the nicotine.

At least a portion of the nicotine present in the composition is synthetic. As used herein, the term “synthetic” means that the identified compound (e.g., nicotine) is prepared through a chemical process that does not include deriving/extracting the nicotine from a naturally occurring source, such as tobacco leaves. The terms “tobacco derived” and “non-synthetic” are used interchangeably herein, and refer to the identified compound or composition that is derived from or extracted from a natural source (such as, for example, tobacco). For example, as used herein, “tobacco derived nicotine” or “non-synthetic nicotine” refers to nicotine derived from or extracted from tobacco leaves, and does not encompass nicotine produced from independent chemical synthesis. In aspects of embodiments of the present invention, the relative portion of the nicotine that is synthetic may be any amount that is sufficient to provide a similar or better taste, impact, and sensation to the user as compared to conventional electronic vaping device compositions that have only tobacco derived nicotine. For example, as a portion of the total amount of nicotine present in the composition, the synthetic nicotine may be present in an amount of about 1 wt % or greater, for example about 5 wt % or greater, about 10 wt % or greater, about 20 wt % or greater, about 30 wt % or greater, about 40 wt % or greater, about 50 wt % or greater, about 60 wt % or greater, about 70 wt % or greater, about 80 wt % or greater, about 90 wt % or greater, about 95 wt % or greater, about 98% or greater, about 99% or greater, about 99.5% or greater, or in a positive amount (i.e., greater than 0%) up to about 100 wt %. When less than 100 wt % of the nicotine in the composition is synthetic, the remaining portion of the nicotine may be tobacco-derived nicotine.

According to some embodiments, the synthetic nicotine in the composition may be prepared by any suitable process, nonlimiting examples of which include the processes disclosed in U.S. Pat. Nos. 8,367,837, 8,378,110 and 8,389,733 and European Patent No. EP 2487172, the entire contents of all of which are incorporated herein by reference. For example, in some embodiments, as described generally in U.S. Pat. Nos. 8,367,837, 8,378,110 and 8,389,733 and European Patent No. EP 2487172 to Divi, et al., 1-(but-1-enyl)pyrrolidin-2-one may be condensed with nicotinic acid ester to give 1(but-1-enyl)-3-nicotinoylpyrrolidin-2-one, which may then be treated with an acid and base to give myosamine, which, in turn, is converted to (R,S)-nicotine by reduction and subsequent N-methylation. An example of this reaction scheme is shown below, reproduced from U.S. Pat. Nos. 8,367,837, 8,378,110 and 8,389,733 and European Patent No. EP 2487172 to Divi, et al.

In some embodiments, the synthetic nicotine in the composition may be prepared by the synthetic route outlined in Scheme 1:

In the synthetic route depicted in Scheme 1, a carbon-carbon bond forming condensation is first performed under anhydrous conditions. In this condensation, an appropriate nicotinate ester (1) is condensed with a suitable N-vinylogous-2-pyrrolidinone (2) under mild conditions, utilizing a suitable dry solvent in combination with a suitable strong base, for example a metal hydride. This condensation gives good yield of the condensation adduct (as its metal salt).

In some embodiments, the condensation reaction mixture utilizes alkyl esters of nicotinic acid in combination with N-vinyl-2-pyrrolidinone, and a metal hydride base in a suitable dry solvent. In some embodiments, the nicotinate alkyl ester comprises short chain alkyl groups (for example, R1 in compound (1) may be C₁₋₃, or in some embodiments C₂). In some embodiments, the N-vinylogous-2-pyrrolidinone may comprise a vinyl substituent with a short chain alkyl group. In some embodiments, R2 in compound (2) may be a short chain (e.g., C₁₋₁₀) alkyl (such as, e.g., methyl, isopropyl, etc.), or in some embodiments, R₂ is hydrogen (H). In some embodiments, the N-vinylogous-2-pyrrolidinone is n-vinyl-2-pyrrolidinone.

The amount (in relative moles) of metal hydride utilized in the condensation reaction mixture with respect to 1 part nicotinate ester is about 0.1 part to about 2.5 parts, for example about 1.2 parts to about 2.1 parts, or about 1.8 parts to about 2 parts. In some embodiments, the mole ratio of metal hydride to nicotinate ester is about 1 to 4, for example about 1:2 to about 1.6:2, or about 2:2. In some embodiments, the metal in the metal hydride may be lithium, potassium or sodium, for example potassium or sodium, or in some embodiments, sodium.

The amount of N-vinylogous-2-pyrolidinone with respect to the amount (in mole equivalents) of nicotinate ester utilized in the condensation reaction mixture may be about 0.1 parts to about 10 parts, for example about 0.5 parts to about 3 parts, or about 1.0 part to about 1.2 parts.

The amount of solvent utilized in the condensation reaction mixture with respect to 1 part (in mole equivalents) nicotinate ester may be about 1 parts to about 15 parts, for example about 3 parts to about 10 parts, about 4 parts to about 8 parts, or about 5 parts to about 7 parts. In some embodiments, the solvent may be anhydrous. Nonlimiting examples of suitable solvents include aromatic hydrocarbon or hydrocarbon solvents, dipolar aprotic solvents (such as, for example, dimethylformamide (DMF)), ethers (such as, for example, ethyl ether, tetrahydrofuran (THF) or tetrahydrofuran derivatives), polyethers (such as, for example, “glyme” or “diglyme”), and combinations thereof. Nonlimiting examples of suitable aromatic hydrocarbons or hydrocarbon solvents include alcohols, toluene, xylenes, benzene, and the like. In some embodiments, for example, the solvent is an alcohol, or an alcohol and ether combination. In some embodiments, the solvent may be THF, or a mixture of DMF and ether, and/or a mixture of DMF and a hydrocarbon or aromatic hydrocarbon. In some embodiments, the solvent may be toluene (or benzene). Alcohols such as ethanol, methanol, and/or propanol may be added to help catalyze the condensation, or the alcohol(s) may be used as the only solvent. If an alcohol is to be used as a solvent or co-solvent in the condensation, then the metals sodium, potassium or lithium may be employed in less than or equal to stoichiometric amounts with respect to the nicotinate ester. In some embodiments, the time of solvent addition is such that a mild effervescence is maintained, and an internal temperature of between 50° C. and 80° C. is maintained throughout the addition process. The time of addition varies with volume, but may take place within a matter of minutes to hours.

After addition of the solvent to the nicotinate ester and N-vinylogous-pyrrolidinone, the condensation reaction mixture becomes greenish. This greenish condensation reaction mixture may be stirred, in some embodiments, under an inert atmosphere for an appropriate amount of time in order to complete the reaction. In some embodiments, the greenish condensation reaction mixture may be heated to an internal temperature of about 40° C. to about 110° C., for example about 60° C. to about 100° C., or about 80° C. to about 95° C.

After reacting the nicotinate ester with the N-vinylogous-2-pyrrolidinone, the condensation reaction mixture may contain a reaction product mixture that includes some unreacted starting material (i.e., nicotinate ester, n-vinylogous-2-pyrrolidinone, sodium hydride) as well as the desired reaction products, i.e., the main condensation product which is the nicotinate-n-vinylogous-2-pyrrolidinone adduct (the condensation adduct, an organic bicyclic compound as the metal salt, e.g., 1-(1-alkenyl)-3-nicotinoylpyrrolidine-2-one, where the alkenyl may be ethenyl in some embodiments), the alcohol as the metal salt, and some alcohol that is displaced from the nicotinate ester as the alcohol.

After completion of the reaction that takes place as a result of the action of the condensation reaction mixture, the reaction product mixture may be either injected (or poured) directly into a solution of acid to form an acid reaction mixture. The acid solution may be a boiling acid solution, or a cold acid aqueous solution. In some embodiments, the acid is an aqueous hydrochloric acid solution. In some embodiments, the normality of the acid solution may be about 3 to about 12, for example about 4 to about 7, or about 5 to about 6.

According to some embodiments, the acid reaction mixture may be prepared by cooling the completed condensation reaction mixture to ambient temperature and then injecting the cooled condensation reaction mixture into a cold solution of acid. The amount of the acid may be about 0.25 parts to about 5 parts, for example about 0.5 parts to about 2 parts, or about 0.75 parts to about 1.5 parts with respect to one part of the condensation reaction mixture.

The reaction of the acid reaction mixture yields a biphasic mixture in which the protonated bicyclic pyridine-pyrrolidinone adduct (i.e., protonated condensation adduct) which is soluble in water and insoluble in the organic solvent is present in the aqueous phase (or layer), and any unreacted pyrrolidinone starting material is in the organic phase (or layer). When the reaction is allowed to settle without agitation, two distinct layers are formed, aqueous and organic (non-aqueous), and the product of the reaction is in the aqueous layer, which aqueous layer is then separated and subjected to further reaction or processing.

After the acid addition, the aqueous and organic (non-aqueous) layers are separated, a concentrated acid is added to the separated aqueous layer to form an aqueous reaction mixture. The aqueous reaction mixture is then heated to reflux for an appropriate period of time to complete the reaction.

The amount of concentrated acid added to separated aqueous layer to form the aqueous reaction mixture may be about 0.15 parts to about 1.5 part, for example about 0.2 part to about 0.5 part, or about 0.25 part to about 0.5 part with respect to 1 part of the separated aqueous layer. In some embodiments, the concentrated acid may be 12N hydrochloric acid (concentrated hydrochloric acid [ca37%]).

After reaction of the aqueous reaction mixture is complete, the aqueous reaction mixture is comprised of water, acid, and product (i.e., the protonated acyclic amine salt, e.g., protonated 3-(4-aminobutanyl-1-one)-pyridine).

After reaction of the aqueous reaction mixture is complete, the aqueous reaction mixture may be cooled to −10° C. to 5° C. Then the acidic aqueous reaction mixture (or solution) may be made strongly basic (e.g., having a pH greater than 9) while keeping the temperature at an appropriate level to maintain the reaction. The result of this reaction is the myosamine reaction mixture, which is comprised of myosamine, base, water, and any remaining unreacted materials from the aqueous reaction mixture, as well as any contaminants natural to the reaction. The resulting basic aqueous reaction mixture is extracted with organic solvent, and then the solvent is distilled off to yield crude myosamine. In some embodiments, the organic solvent may be dichloromethane. In some embodiments, the amount of organic solvent may be about 1 part to about 10 parts with respect to the amount of the basic aqueous reaction mixture, for example about 1.5 parts to about 5 parts, or about 2 parts to about 4 parts with respect to the basic aqueous reaction mixture.

In some embodiments, the completed condensation reaction may be injected directly into a hot solution of hydrochloric acid (instead of the cold acid solution described above), resulting in a heterogeneous acid reaction mixture. The heterogeneous acid reaction mixture may be heated using an external bath to enable vigorous reflux, and the vigorous reflux may be continued until the reaction is complete. In embodiments of this hot acid alternative, the solvent for the condensation reaction mixture may be toluene or xylene, or a high boiling point solvent such as diglyme.

In order to reduce the crude myosamine product to a crude nornicotine product, a suitable hydrogenation catalyst is added in a suitable amount to the crude myosamine (3) in solution with an appropriate solvent to form a myosamine reaction mixture. To complete the reduction of myosamine to nornicotine, the myosamine reaction mixture is submitted to an atmosphere of hydrogen gas at a pressure greater than or equal to ambient pressure, but not high enough to reduce the carbons in the pyridine ring.

In some embodiments, the solvent for the myosamine reaction mixture may be an alcoholic solvent, for example, ethanol or isopropanol, although other solvents known in the art of hydrogenation can also be employed. The amount of solvent may be about 3 parts to about 98 parts, for example about 4 parts to about 60 parts, or about 5 parts to about 20 parts solvent with respect to 1 part crude myosamine. In some embodiments, the suitable hydrogenation catalyst may include 10% palladium on carbon, but other catalysts common to the art of catalytic hydrogenation may also be employed, either as a co-catalyst, or as the sole catalyst. The pressure of the hydrogen gas can be about ambient pressure to about 100 atmospheres, for example about ambient pressure to about 75 atmospheres, or about 10 to about 50 atmospheres.

In some embodiments, the myosamine reaction mixture may include a borohydride salt as the reducing agent rather than a hydrogenation catalyst, and the myosamine reaction mixture may undergo different reaction conditions suitable to effect reduction of the myosamine to nornicotine using the borohydride salt.

Completion of the reaction of the myosamine reaction mixture yields a crude nornicotine reaction mixture that includes nornicotine (reduction product), catalyst and solvent, as well as any unreacted starting material (crude myosamine) and unwanted reaction contaminants. Crude nornicotine product (4) is extracted from the crude nornicotine reaction mixture using known extraction methods.

Water, formic acid and formaldehyde are added to the crude nornicotine (4) product to form a crude nicotine reaction mixture. The crude nicotine reaction mixture is heated to an appropriate temperature for a duration which allows for completion of the methylation reaction that affords crude Nicotine in good yield.

At the completion of the reaction of the crude nicotine reaction mixture, the resulting mixture contains crude RS-Nicotine product, solvent (water), and any unreacted starting material including formaldehyde and formic acid, as well as reaction contaminating by-products.

The product of the crude nicotine reaction mixture, i.e., crude RS-Nicotine, may be subjected to at least one high vacuum distillation to give pure (i.e., greater than 95% pure, for example greater than 97% pure, greater than 99% pure, or greater than 99.5% pure) RS-Nicotine as a clear, colorless non-viscous liquor in good overall yield.

The synthetic nicotine produced according to the above-described chemical synthesis is substantially free or completely free of certain contaminants typically found in the natural nicotine derived from tobacco leaves. In some embodiments, the synthetic nicotine may be substantially free of these contaminants, such that the combined amount of these contaminants in the synthetic nicotine may be more than 0 wt % but less than 0.5 wt %, for example less than 0.2 wt %, less than 0.01 wt %, less than 0.001 wt %, less than 0.0001 wt %, or less than 0.00001 wt % based on the total weight of the synthetic nicotine. As discussed above, completely free or free of these contaminants means that the synthetic nicotine includes no measurable amount of these contaminants, i.e., 0 wt % (or none). In some embodiments, the synthetic nicotine is substantially free or completely free of contaminants such as alkaloid compounds, which may be found in nicotine derived from tobacco. For example, the synthetic nicotine may be substantially free or completely free of one or more or all of nicotine-1′-N-oxide, nicotyrine, nornicotyrine, 2′,3-bipyridyl, anabasine, and anatabine. While these contaminants may be among the most common impurities or contaminants in tobacco-derived nicotine, other naturally occurring contaminants or impurities may be present in tobacco-derived nicotine, and the synthetic nicotine according to embodiments of the present invention is substantially free or completely free of those contaminants and impurities as well.

However, while the synthetic nicotine according to embodiments of the present invention may be substantially free or completely free of certain contaminants normally found in tobacco-derived nicotine, as discussed above, the synthetic nicotine may include certain other impurities or contaminants resulting from the synthetic route. Although such contaminants and impurities may be present in the synthetic nicotine according to embodiments of the present invention, these impurities are not generally present in tobacco-derived or naturally sourced nicotine. Indeed, the contaminants/impurities found in naturally sourced (or tobacco-derived) nicotine are significantly different than those potentially found in the synthetic nicotine according to embodiments of the present invention. For example, the contaminants or impurities present in the synthetic nicotine according to embodiments of the present invention may include one or more or all of myosamine, nornicotine, water, and the solvents (discussed above) used in the various reactions of the synthesis scheme. Additionally, in some embodiments, the contaminants or impurities present in the synthetic nicotine may include one or more or all of 1-keto-5-methylamino, or 1-hydroxy-5-methylamino-2-pyridine. As used herein, the terms “synthetic contaminants,” “synthetic impurities,” and like terms, are used interchangeably, and refer to these contaminants and/or impurities found in the synthetic nicotine according to embodiments of the present invention but not typically found in naturally sourced (or tobacco-derived) nicotine.

For example, based on the total weight of the synthetic nicotine, the synthetic nicotine may include about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 5 wt %, for example about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 1 wt %, about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 0.5 wt % myosamine. In some embodiments, based on the total weight of the synthetic nicotine, the synthetic nicotine may include about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 5 wt %, for example about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 3 wt %, or about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 1 wt % nornicotine. In some embodiments, based on the total weight of the synthetic nicotine, the synthetic nicotine may include about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 5 wt %, for example about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 3 wt %, or about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 1 wt % solvent. Also, in some embodiments, based on the total weight of the synthetic nicotine, the synthetic nicotine may include about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 5 wt %, for example about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 3 wt %, or about 0 wt % (i.e., an undetectable, or unmeasurable amount) to about 1 wt % water.

The above-described synthesis of nicotine produces a racemic mixture, i.e., a 50-50 mixture of the R and S isomers of nicotine. Thus, in some embodiments, the synthetic nicotine includes a ratio of the R-isomer to the S-isomer of 1:1. However, in some embodiments, the ratio of the R-isomer to the S-isomer can be manipulated through further resolution of the synthetic nicotine. For example, the synthetic nicotine may have a ratio of the R-isomer to the S-isomer of about 1:1 to about 1:1000, about 1:1.1 to about 1:100, about 1:2 to about 1:5, about 1:4 to about 1:9, or about 1:5 to about 1:7. In some embodiments, the synthetic nicotine may include a ratio of the R-isomer to the S-isomer of about 1:1 to about 1000:1, about 1.1:1 to about 100:1, about 2:1 to about 5:1, about 4:1 to about 9:1, or about 5:1 to about 7:1.

In some exemplary embodiments, for example, the synthetic nicotine includes a ratio of the S-isomer to the R-isomer of less than 50:1, for example 45:1 or lower, 40:1 or lower, or 35:1 or lower. In some embodiments, the synthetic nicotine may include a ratio of the R-isomer to the S-isomer of less than 50:1, for example 45:1 or lower, 40:1 or lower, or 35:1 or lower. Additionally, in some embodiments, the synthetic nicotine may include the R-isomer in an amount greater than 5 wt %, for example, greater than 7 wt %, or greater than 10 wt %. In some embodiments, the synthetic nicotine may include the S-isomer in an amount greater than 5 wt %, for example, greater than 7 wt %, or greater than 10 wt %. In some embodiments, the synthetic nicotine includes more R-isomer than S-isomer, and in some embodiments, the synthetic nicotine includes more S-isomer than R-isomer.

This ratio of R/S isomers in the synthetic product is yet another characteristic that distinguishes the synthetic nicotine according to embodiments of the present invention from natural or tobacco-derived nicotine. Indeed, a simple test to determine chirality of the sample can be performed in order to determine whether the sample includes natural nicotine or a synthetic nicotine according to embodiments of the invention. Techniques for determining chirality or optical rotation of a sample are known to those of ordinary skill in the art, and the ordinary artisan would be readily capable of selecting an appropriate technique and carrying out that technique to determine chirality or optical rotation. One nonlimiting example of such a technique is high performance liquid chromatography (HPLC) using a chiral column. For example, the optical rotation of the sample may first be determined by any suitable technique (which are known to those of ordinary skill in the art), and then the sample may be run through the chiral column and the results compared to the USP standard for tobacco-derived or natural nicotine.

The synthetic nicotine containing the racemic mixture of R and S isomers may be resolved to have these relative amounts of the R and S isomers by any suitable resolution techniques, which techniques are known to those skilled in the art (e.g., crystallization, chromatography, etc.). Additionally, in some embodiments, the synthesized nicotine may be fully resolved to yield either pure R-isomer or pure S-isomer. As used herein, the term “pure” as used in defining the isomeric composition of the synthetic nicotine, refers to a percentage of the identified isomer of greater than 97%, for example greater than 98%, and in some embodiments greater than 99%. For example, a “pure S isomer” synthetic nicotine includes a synthetic nicotine that has been resolved to include a ratio of S isomer to R isomer of greater than 97:3, for example greater than 98:2, and in some embodiments, greater than 99:1. Similarly, a “pure R isomer” synthetic nicotine includes a synthetic nicotine that has been resolved to include a ratio of R isomer to S isomer of greater than 97:3, for example greater than 98:2, and in some embodiments, greater than 99:1. In some embodiments, however, a pure R isomer may include 100% R isomer with 0% S isomer, and a pure S isomer may include 100% S isomer with 0% R isomer.

As noted above, any suitable resolution technique may be used to resolve the synthetic nicotine composition, which techniques are known to those of ordinary skill in the art. Some nonlimiting examples of resolution techniques include those described in Divi et al., U.S. Patent Publication No. 2012/0197022, filed Apr. 6, 2011, Aceto, et al., J. Med. Chem., “Optically Pure (+)-Nicotine from (±)-Nicotine and Biological Comparisons with (−)-Nicotine vol. 22, pgs. 174-177 (1979), and DeTraglia et al., “Separation of D-(+)-Nicotine from a Racemic Mixture by Stereospecific Degradation of the L-(−) Isomer with Pseudomonas putida,” Applied and Environmental Microbiology, vol. 39, pgs. 1067-1069 (1980), the entire contents of all of which are incorporated herein by reference. For example, as described in Aceto et al., resolution of the racemic mixture may be accomplished using D-tartaric acid, and as described in DeTraglia et al., resolution can be accomplished using pseudomonas putida. In addition, in some embodiments, resolution of the racemic mixture may be accomplished using (+)-O,O′-di-p-toluoyl-D-tartaric acid. Additionally, as described in Divi et al., resolution of the racemic mixture may be accomplished by diastereomeric salt formation using dibenzoyl-D-tartaric acid and dibenzoyl-L-tartaric acid to achieve separation.

In some embodiments, however, the racemic mixture may be blended or mixed with suitable added amounts of pure R isomer or pure S isomer, which pure isomers would typically be prepared via enantioselective synthetic pathways. Notably, naturally sourced nicotine (i.e., that derived from tobacco leaves) generally has an undetectable or small amount of the R isomer, and typically the naturally sourced tobacco mainly includes the S isomer. Indeed, naturally sourced tobacco typically has an S to R isomer ratio of greater than 50:1.

As discussed above, according to some embodiments of the present invention, the synthetic nicotine may include a mixture of the R and S isomers, whether racemic or otherwise. As would be understood by those of ordinary skill in the art, tobacco-derived (or naturally sourced) nicotine typically has greater than 95 wt % of the S isomer, and therefore is optically active. Indeed, when measured using a standard polarimeter, the tobacco-derived nicotine (having 95 wt % or greater S nicotine isomer) registers a negative optical rotation which is typically greater than 125°. In contrast, according to embodiments of the present invention, the synthetic nicotine may include a racemic (or 1:1) mixture of the R and S isomers, yielding a nicotine having no optical rotation. Additionally, in embodiments of the present invention in which the synthetic nicotine includes a non-racemic mixture of the R and S isomers, the synthetic product will register an optical rotation that is different from the optical rotation of tobacco-derived nicotine (i.e., due to the presence of the R isomer, which generally has an opposite optical rotation than that of the S isomer).

As discussed above, tobacco-derived (or naturally sourced) nicotine may include one or more or all of the following impurities: nicotine-1′-N-oxide, nicotyrine, nornicotyrine, 2′,3-bipyridyl, cotinine, anabasine, anatabine, nornicotine, and myosamine. For example, tobacco derived nicotine may comprise 99.5 wt % nicotine, 0.1 wt % nornicotine, 0.15 wt % myosamine, and 0.1 wt % cotinine. According to some embodiments of the present invention, as described above, the vaping composition or vaping solution may include both the synthetic nicotine described above and an amount of naturally sourced (or tobacco-derived) nicotine. In these embodiments of the vaping composition including the naturally sourced nicotine, the portion of the composition making up the tobacco-derived nicotine may include these components (or contaminants) in, e.g., the above amounts. However, as would be appreciated by those of ordinary skill in the art, because the naturally sourced nicotine (or tobacco-derived nicotine) makes up only a portion of the vaping composition or vaping solution, the amount of these natural tobacco contaminants in the overall vaping composition is significantly lower than the amounts reported above, and significantly lower than the amounts in comparable vaping compositions or solutions using larger portions of (or all) naturally sourced nicotine.

In addition to the synthetic nicotine and/or naturally sourced nicotine discussed above, the composition for use in electronic vaping devices (i.e., the vaping composition or vaping solution) may further comprise, consist essentially of, or consist of one or more pharmaceutically acceptable excipients, additives or solvents. Nonlimiting examples of such excipients, additives and/or solvents include water, organic solvents, sweetening and/or flavoring agents, pH adjusting agents and the like. Nonlimiting examples of solvents that may be used in liquid vaping compositions include water, and alcohols such as 1,2-propylene glycol (PG or MPG), ethanol, ethyl acetate, 1-3 propanediol, glycerin (e.g., vegetable glycerin) and the like. The solvent may include a single solvent or may include a combination of two or more solvents. The amount of solvent present may be about 50 wt % to about 99.99 wt %, for example about 75 wt % to about 99 wt %, or about 85 wt % to about 98 wt % based on the total weight of the composition.

In some embodiments, the vaping composition may include water as a solvent. The amount of water present in the vaping composition may be about 0.1 to about 10 wt %, for example about 0.5 to about 5 wt %, based on the total weight of the vaping composition.

In some embodiments, the vaping composition may include glycerin as a solvent, and the glycerin may be a Kosher vegetable glycerin having a purity greater than 99%, for example greater than 99.5%, or greater than 99.9%. The glycerin may be odorless, colorless and have a slightly sweet taste.

In some embodiments, the vaping composition may include propylene glycol as a solvent, and the propylene glycol may be USP grade and have a purity greater than 99%, for example greater than 99.5%, or greater than 99.99%. The propylene glycol may be odorless and colorless, and essentially tasteless. In some embodiments, the vaping composition may include a solvent that comprises, consists essentially of, or consists of glycerin and propylene glycol.

In some embodiments, the pH of the vaping composition may be adjusted by the addition of pharmacologically or pharmaceutically acceptable acids as pH adjusting agents. In some embodiments, the acid pH adjusting agent may be an inorganic acid. Nonlimiting examples of suitable inorganic acid pH adjusting agents include: hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and/or phosphoric acid. In some embodiments, the inorganic acid may include hydrochloric acid and/or sulfuric acid (i.e., an inorganic acid or a mixture of inorganic acids).

In some embodiments, the acid pH adjusting agent may be an organic acid. Nonlimiting examples of suitable organic acids include: lactic acid, ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid, and the like. In some embodiments, for example, the organic acid may be lactic acid, ascorbic acid, fumaric acid and/or citric acid (i.e., an organic acid or a mixture of organic acids). For example, in some embodiments, the organic acid includes citric acid and/or lactic acid.

In some embodiments, the acid pH adjusting agent may be an acid which forms an acid addition salt with the active substance. Also, if desired, a single acid pH adjusting agent may be used, or a mixture of two or more acid pH adjusting agents may be used. Indeed, some acids have additional properties that make them desirable for inclusion in the vaping composition. For example, some acids may have pH adjusting (or acidifying) properties in addition to auxiliary or additional properties, such as, e.g. flavoring properties or antioxidant properties. Some nonlimiting examples of such dual function acids include citric acid and ascorbic acid.

In some embodiments, the pH adjusting agent may be basic, or the vaping composition may include an additional pH adjusting agent that is basic (e.g., in addition to the acidic pH adjusting agent). For example, a basic pH adjusting agent may be used or desired to more precisely titrate the pH of the vaping composition. Accordingly, in some embodiments, the pH adjusting agent may include (or further include) a basic pH adjusting agent, which may include a pharmacologically acceptable base. Nonlimiting examples of suitable such bases include alkali metal hydroxides and alkali metal carbonates. In some embodiments, the alkali ion in the alkali metal hydroxides or carbonates may be sodium. In embodiments in which such a basic pH adjusting agent is used, as would be understood by those of ordinary skill in the art, care must be taken to ensure that the resulting salts, which are then contained in the finished pharmaceutical formulation, are pharmacologically compatible with the abovementioned acid of the acid pH adjusting agent.

As would be understood by those skilled in the art, the amount of the pH adjusting agent (whether acid or base) will depend on the desired target pH and the starting pH of the composition. Indeed, pH adjustment and titration techniques and addition amounts are well within the knowledge and skill of the ordinary artisan in this field.

In some embodiments, as discussed above, the vaping composition may further include a pharmacologically or pharmaceutically acceptable excipient. The excipient may include any of a number of compounds, some nonlimiting examples of which include antioxidants, such as ascorbic acid (which can also be used to adjust the pH as discussed above), vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body. Other nonlimiting examples of suitable excipients include preservatives, which can be added to protect the formulation from contamination by, for example, pathogenic bacteria. Any suitable preservative may be used, including those known in the art. Some nonlimiting examples of suitable preservatives include benzalkonium chloride, benzoic acid or benzoates such as sodium benzoate. In some embodiments, the preservative may include benzalkonium chloride. Any suitable amount of the preservative may also be used, which amount (or concentration) would be known to those skilled in the art.

In some embodiments, the vaping composition may further comprise a sweetening and/or flavoring agent. Any suitable such sweetener and/or flavoring agent may be used, some nonlimiting examples of which include peppermint, menthol, wintergreen, spearmint, propolis, eucalyptus, cinnamon, or the like. Some additional nonlimiting examples of suitable flavorants or sweeteners include those derived from fruits, tobacco itself, liquor, coffee and confectionaries. The amount of the sweetener and/or flavorant may be about 0 wt % (e.g. no flavorant is present, or no flavorant is added) to about 40 wt %, for example about 1 wt % to about 30 wt %, about 5 wt % to about 20 wt %, or about 10 wt % to about 15 wt %, based on the total weight of the vaping composition. In some embodiments, the amount of the sweetener and/or flavorant may be about 10 wt % based on the total weight of the vaping composition.

In some embodiments, a vaping composition may comprise, consist essentially of, or consist of nicotine, propylene glycol, glycerin, nut oils, drinking alcohol (such as vodka), and flavorings (e.g., those designed for use in vaping devices). The amount of nicotine in the vaping composition may be as described above with respect to a wholly synthetic nicotine source, a combination of both synthetic nicotine (e.g., synthetic S-nicotine or synthetic R-nicotine) and tobacco derived (or naturally sourced) nicotine, or an R,S isomeric mixture or blend (e.g., a racemic mixture, or any other mixture of the R and S isomers). The amount of propylene glycol in the vaping composition may be about 0 wt % (i.e., not present at all, or not added) to about 99 wt %, for example about 10 wt % to about 70%, or about 30 wt % to about 50%, based on the total weight of the vaping composition. The amount of glycerin in the vaping composition may be about 0 wt % (i.e., not present at all, or not added) to about 99 wt %, for example about 30 wt % to about 90 wt %, or about 40 wt % to about 70 wt %, based on the total weight of the vaping composition. The amount of nut oil in the vaping composition may be about 0 wt % (i.e., not present at all, or not added) to about 20 wt %, for example about 0.5 wt % to about 10 wt %, or about 1.0 wt % to about 5.0 wt %, based on the total weight of the vaping composition. The amount of drinking alcohol (such as vodka) may be about 0 wt % (i.e., not present at all, or not added) to about 99 wt %, for example about 30 wt % to about 90 wt %, or about 40 wt % to about 70 wt %, based on the total weight of the vaping composition. The amount of flavorings in the vaping composition may be about 0 wt % (i.e., not present at all, or not added) to about 40 wt %, for example about 1.0 wt % to about 30 wt %, about 5 wt % to about 20 wt %, or about 10 wt % to about 15 wt %, based on the total weight of the vaping composition.

It has been surprisingly found that the vaping compositions according to embodiments of the present invention including a portion of synthetic nicotine has suitable and/or enhanced physiological activity on the human system, including neuroactivity, as well as suitable and/or enhanced sensory appeal (e.g., mouthfeel, throatfeel, etc.) as compared to compositions including only nicotine derived from tobacco (or naturally sourced nicotine) as the nicotine component. Indeed, smoker/vaporizer uses have found that the compositions according to the present invention including at least a portion of synthetic nicotine to be preferable to compositions using only nicotine derived from tobacco (or naturally sourced nicotine) as the nicotine component.

Because the vaping compositions described herein have fewer of the contaminants associated with tobacco-derived nicotine, smaller amounts (if any at all) of flavorants are needed in the compositions. In particular, smaller amounts of flavorants are needed to mask the bitterness and smell of comparable compositions comprising only tobacco-derived nicotine as the nicotine component. In some embodiments, the vaping composition is substantially free of flavorants.

Using smaller amounts of flavorants (or substantially no flavorants) provides a mechanical benefit to the electronic vaping device. Specifically, the use of smaller amounts of flavorants leads to less wear on the coil or heating element of the vaporizer. Because flavorants tend to be sticky, oily or more viscous than the other components in the vaping composition, the addition of larger amounts of flavorants causes the coil (or heating element) to work harder to heat the vaping composition. Also, because of the sticky, oily, viscous properties of the flavorants, compositions having larger amounts of flavorants tend to have larger amounts of buildup on the coil, which also increases wear on the coil, and decreases the working life of the coil (and device). In contrast, in the vaping compositions according to embodiments of the present invention, smaller amounts of the flavorants are used, reducing the wear on the coil, and the potential for buildup on the coil. As a result, the vaping compositions according to embodiments of the present invention can increase the working life of the coil or heating element, and thus the life of the vaping device.

In accordance with aspects of embodiments of the present invention, a (1) 50-50 RS synthetic nicotine provides the same or better sensory impact as “S” nicotine derived from tobacco. Similarly, a (2) racemic synthetic nicotine is neurologically effective, and in many cases exhibits superior neurological effect to that of tobacco-derived (“S”) nicotine. Also, the above-disclosed blends of synthetic RS nicotine with synthetic or non-synthetic tobacco-derived nicotine, according to embodiments of the present invention, have improved sensory impact as well as neurological impact on the user as compared to vaping compositions having only tobacco-derived nicotine as the source of nicotine. Additionally, having fewer tobacco alkaloids in the vaping composition increases the shelf life of the composition and maintains visual clarity of product (e.g., a colorless or transparent appearance).

According to some embodiments of the present invention, an electronic vaping device utilizes the vaping compositions described above. Any suitable electronic vaping device may use the vaping compositions according to embodiments of the present invention, some nonlimiting examples of which include single-use (or disposable) e-cigarettes, refillable devices that can be refilled with a vaping (e.g., liquid) composition, and/or reusable devices having removable and replaceable cartridges containing a vaping (e.g., liquid) composition.

According to embodiments of the present invention, a vaping device may include the vaping compositions described herein and an atomizer (or a heating coil or other heat source) for vaporizing the composition. For example, an e-cigarette according to embodiments of the present invention is shown in FIG. 1. As shown in FIG. 1, an external shell 14 has an air inlet 4 and houses an LED 1, cell 2, electronic circuit board 3, normal pressure cavity 5, sensor 6, vapor-liquid separator 7, atomizer 9, liquid-supplying bottle 11, mouthpiece 15, microswitch 16, gas vent 17, and air passage 18. The electronic circuit board 3 has an electronic switching circuit and a high frequency generator. The sensor 6 includes a negative pressure cavity 8 separated from the sensor 6 by a ripple film. The atomizer 9 has an atomization cavity 10. A retaining ring 13 locks the liquid-supplying bottle 11 between one side of the liquid-supplying bottle 11 and the shell 14. The other side of the liquid-supplying bottle includes an aerosol passage 12. The construction, function, and workings of e-cigarettes and vaping devices are known to those skilled in the art, and additional details of these devices are described in U.S. Pat. No. 7,832,410 B2 to Hon, the entire content of which is incorporated herein by reference. The vaping compositions according to embodiments of the present invention may be used with any known type of electronic vaping device including devices referred in the art as direct coil vaporizers, heated plate vaporizers, ceramic or metal bed/bowl heating vaporizers, ultrasonic agitation vaporizers, and electronic heated nail/spike vaporizers. The heating range of the heating elements during operation of these devices may be about 100° C. to about 460° C.

Examples

The following Examples are provided for illustrative purposes only, and are not intended to limit the scope of any of the embodiments of the present invention.

Synthesis Example 1—R,S Nicotine Synthesis

1 equivalent of potassium hydride was added to a stirred solution of 1-vinyl-2-pyrrolidinone (2) in dry THF under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 20 minutes, then ethyl nicotinate (1 equivalent) was added and the resulting mixture was stirred for 24 hours at 65 degrees centigrade. The reaction was cooled and then acidified with 5% HCl, and then concentrated HCl was added and the resulting solution was refluxed for 48 hours. The pH was adjusted to 13 with sodium hydroxide, and the aqueous and organic layers of the resulting biphasic solution were separated three times using equal volumes of dichloromethane. The combined extracts from the separation were dried over sodium sulfate, filtered and the solvent evaporated to give an amorphous material. The amorphous material was taken up in 3 parts ethanol, and then palladium-on-carbon was added (about 10%) and the resulting mixture was subjected to hydrogen pressure for 6 hours (greater than 25 atmospheres). The resulting residue was diluted with more ethanol and filtered through celite. The solvent was evaporated to dryness under vacuum with minimal heat, and then the residue was taken up in a formic acid/formaldehyde solution (1:1). The resulting mixture was heated to an internal temperature of 90 degrees Celsius and maintained at this temperature over a period of 12 hours, and then cooled and neutralized with sodium hydroxide to a pH of greater than 10, and then extracted with dichloromethane and dried over sodium sulfate, filtered and concentrated to give a brown oil. This oil was vacuum distilled to give pure RS Nicotine.

Synthesis Example 2—R,S Nicotine Synthesis

1.2 equivalent of sodium hydride was added to a stirred solution of 1-vinyl-2-pyrrolidinone (2) in dry THF/DMF (3/1) under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 20 minutes, then ethyl nicotinate (1 equivalent) was added, and the resulting mixture was stirred for 24 hours at 65 degrees centigrade. The reaction was cooled and then acidified with 5% HCl, and then concentrated HCl was added, and the resulting mixture was refluxed for 48 hours. The pH was adjusted to 6 with sodium hydroxide, and then excess dichloromethane was added and the layers were separated. The aqueous layer was extracted twice with excess dichloromethane, and the extracts were combined and washed with water, and then dried over sodium sulfate. The solution was then filtered and the solvent removed using vacuum to yield a brownish solid. This solid was dissolved in ethanol (about 5 to about 10 parts), and then 0.5 parts palladium on carbon was added and the resulting mixture was subjected to hydrogen pressure for 6 hours (greater than 25 atmospheres). The resulting residue was diluted with more ethanol and filtered through celite. The solvent was evaporated to dryness under vacuum with minimal heat, and then the residue was taken up in 3 parts formic acid and 3 parts formaldehyde, and the resulting solution was heated to an internal temperature of about 90 to about 95 degrees centigrade and maintained at this temperature over a period of 24 hours. The reaction was cooled and then vacuum distilled to yield pure RS nicotine as a clear, colorless non-viscous oil.

Synthesis Example 3—R,S Nicotine Synthesis

1 equivalent of potassium hydride was added to a stirred solution of 1-vinyl-2-pyrrolidinone (2) in dry DMF under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 20 minutes, then ethyl nicotinate (1 equivalent) was added and the resulting mixture was stirred for 24 hours at 65 degrees centigrade. The reaction was cooled and then acidified with 5% HCl and then refluxed for 48 hours. The pH was adjusted to 6 with sodium hydroxide, and then a suspension of sodium borohydride in isopropanol was added in excess and the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was then acidified to a pH of about 3 with 5% HCl, and then stirred for about 15 minutes. 10 parts dichloromethane was added and the layers were separated. The organic layer was dried over sodium sulfate and filtered, and then 1.1 equivalents of potassium carbonate was added, and then 1.1 equivalents of methyl iodide was added and the reaction mixture was stirred for 24 hours and filtered, and the solvent was removed to yield an oil which was vacuum distilled to yield pure RS nicotine.

Synthesis Example 4—R,S Nicotine Synthesis

1 equivalent of potassium hydride was added to a stirred solution of 1-vinyl-2-pyrrolidinone (2) in dry THF under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for about 20 minutes, then ethyl nicotinate (1 equivalent) was added and the resulting mixture was stirred for 24 hours at 65 degrees centigrade. The reaction was cooled and then acidified with 5% HCl and then concentrated HCl was added and the resulting mixture was refluxed for 48 hours. The pH was adjusted to 6 with sodium hydroxide, and then a suspension of sodium borohydride in isopropanol was added in excess and the reaction mixture was stirred for 24 hours at room temperature. About 10 parts formic acid and about 10 parts formaldehyde were then added, and the resulting solution was stirred at about 100 degrees centigrade for 24 hours, cooled, and then brought to a pH of about 12 by addition of a sodium hydroxide solution. The layers were then separated and the aqueous layer was washed many times with dichloromethane. The organic extracts were dried over sodium sulfate and the solvent was removed. The resulting crude oil was vacuum distilled to yield pure RS nicotine as a clear and colorless non viscous liquor.

Synthesis Example 5—R,S Nicotine Synthesis

1.2 equivalents of sodium hydride (60% dispersion in oil) was added to a stirred solution of 1-vinyl-2-pyrrolidinone (2) in toluene, and then a concentrated solution of ethyl nicotinate (1 equivalent) in toluene was added drop-wise over 20 min. The resulting mixture was heated to reflux for 3 hours. This crude reaction mixture was cooled in an ice bath, and then excess concentrated hydrochloric acid was added and the resulting solution was heated to an internal temperature of about 85 to about 110 degrees Celsius and maintained at this temperature over a period of 12 hours. The reaction mixture was then cooled to room temperature, and the upper toluene layer removed. Sodium hydroxide was added to the acidic aqueous layer until the pH was greater than 12, and then the pH was adjusted to about 8 with HCl. 2.5 equivalents of sodium borohydride solution in isopropanol (stabilized with sodium hydroxide) were added to the stirred solution, and the resulting mixture was stirred for 6 hours (until the reaction was completed). Excess formic acid and formaldehyde was then added, and the resulting mixture was refluxed for 10 hours, and then brought to neutral or slightly basic pH with sodium hydroxide, and then the solvents were removed by vacuum and the remaining residue was vacuumed distilled to yield pure R,S, Nicotine (boiling point=74 to 76 degrees Celsius @ 0.5 mmHg).

Synthesis Example 6—Myosamine Synthesis

Sodium hydride (1.25 Kg, 31.2 mole) was added to a stirred solution of toluene (10 L) in an inert atmosphere (dry nitrogen or argon gas) and stirred for about 15 minutes at room temperature. Then, a solution of n-vinyl pyrrolidinone (2 kg, 18.02 mole) in 1 L of toluene was added over 15 minutes via funnel addition, and the resulting mixture was stirred at ambient temperature for about 15 minutes. Then, a solution of ethyl nicotinate (2.5 Kg, 16.56 mole) in 2 L toluene was added in portions over a two hour period. The mildly effervescent exothermic reaction mixture turned a light rose color and then a light green precipitant formed as the exothermic reaction maintained itself at about 60 to about 65° C. After the addition was complete, the reaction mixture was heated to an internal temperature of about 85° C. and maintained at this temperature for about 16 hours, then cooled to room temperature yielding a greenish heterogeneous mixture. This greenish heterogeneous mixture flows well and can be pumped through a ½″ polyethylene tubing using a diaphragm pump. The greenish heterogeneous mixture was added, in about 250 mL portions, to 25 L of a boiling solution of 6N HCl. The addition took place with vigorous effervescence, which subsided within a few minutes after addition of the aliquot of the reaction mixture to the hot HCl. After all the reaction mixture was added, the resulting dark brown biphasic mixture was stirred under reflux for an additional hour. Then, the reaction mixture was cooled, and the layers were separated. The aqueous layer was cooled, made basic (i.e., having a pH greater than 10) using NaOH (50%), and then extracted 3 times with 8 L of dichloromethane. The solvent was then removed via vacuum distillation (temperature of the bath was about 45 degrees centigrade) to yield crude myosamine as a dark brown, non-viscous oil.

Synthesis Example 7—Nornicotine Synthesis

The total crude myosamine from Synthesis Example 6 was taken up in 16 L of ethanol. 250 grams of 10% palladium-on-carbon was added, and the resulting mixture was stirred in a hydrogen atmosphere for 12 hours, followed by filtering using celite, and washing with ethanol. The ethanol was removed by vacuum to give crude nornicotine as a dark brown non-viscous oil.

Synthesis Example 8—R,S Nicotine Synthesis

2.0 Kg of formaldehyde (37%) and 1.5 Kg of formic acid (85%) were added to the crude nornicotine from Synthesis Example 7. The resulting brown solution was heated to an internal temperature of 85 degrees centigrade and maintained at this temperature for 15 hours, and then cooled to ambient temperature. The resulting solution was chilled to about 5 degrees centigrade, and then made basic by addition of NaOH. The resulting solution was then extracted 3 times with 8 L of dichloromethane, and the solvent was removed by vacuum. Pure R,S-nicotine was obtained using high vacuum distillation (i.e., 75 to 76 @ 0.5 mmHg) to yield a clear, colorless non-viscous oil (about 31% overall yield from ethyl nicotinate).

Synthesis Example 9—Synthesis of Nornicotine

The total crude myosamine from Synthesis Example 6 was taken up in 16 L methanol and 4 L of acetic acid. The resulting solution was cooled to an internal temperature of −40 degrees centigrade, and then 700 grams of sodium borohydride (granular) was added in portions over 1 hour. The reaction mixture was allowed to warm to room temperature with stirring, and was then submitted to vacuum distillation to remove most of the solvent. The resulting liquor was added to 25 L of water, and the resulting solution was brought to a pH greater than 10 with NaOH. The resulting solution was extracted three times with 15 L of dichloromethane, and the combined extracts were subjected to medium vacuum distillation to give crude nornicotine as a crude non-viscous dark brown colored oil.

Synthesis Example 10—Synthesis of R,S Nicotine

A solution of N-vinyl pyrrolidinone (4.5 kg) in 2.5 Kg of toluene was added to 2.5 Kg of Sodium Hydride (60% dispersion in mineral oil) as a stirred suspension in 20 L of toluene. The resulting mixture was stirred for about 15 minutes at room temperature. 5 Kg of ethyl nicotinate in 10 Kg of toluene was added to the resulting mixture in portions and by a constant slow stream of liquor (light golden color). The exothermic reaction was controlled at an internal temperature of about 60° C. by controlling the rate of addition of the ethyl nicotinate—toluene solution. After addition of about one third of the ethyl nicotinate, a green precipitate was formed. After addition was completed, the green heterogeneous mixture was heated to an internal temperature of about 85° C. and maintained at this temperature for about 12 hours. The resulting solution was injected into a precooled solution of 30 L of 4N HCl at 0° C. followed by vigorous stirring for about 5 minutes. The layers were separated, and the toluene layer was washed once with 2.5 Kg of 4N HCl. 8 L of concentrated HCl was added to the combined acidic aqueous layers, and the reaction mixture was heated to boiling and maintained at this temperature for about 3 hours (or until the reaction was completed, as determined by thin layer chromatography (TLC)). The reaction mixture was cooled to 0° C., and then neutralized with 50% sodium hydroxide solution while not allowing the internal temperature to go above 35 to 40 degrees centigrade. The pH was made very basic by addition of a sodium hydroxide solution (50%) until the pH reached 11 to 13 (as indicated by a blue color change on litmus paper). The resulting solution was extracted 4 times with 15 L of dichloromethane, and the combined extracts were subjected to medium vacuum distillation to yield myosamine as a non-viscous brownish oil.

40 L of anhydrous ethanol was added to the crude myosamine product, and the resulting solution was added to 2 Kg of 10% palladium-on-carbon. The resulting mixture was subjected to hydrogen pressure of 50 atm. The reaction was completed within 12 hours. The resulting heterogeneous mixture was filtered through celite, and then washed twice with 10 L of ethanol. The combined ethanolic solutions of the crude nornicotine product was subjected to vacuum distillation (29 inches Hg) at below 50° C., and then the crude dark brown oil was taken up in 10 L water. A solution of 5 L of formaldehyde solution (37%) with 4 L of formic acid (85%) was added to the resulting solution, and the mixture was heated to an internal temperature of 90° C. and maintained at this temperature for 20 hours. The reaction mixture was cooled to −5° C., and then made basic (i.e., a pH greater than 10) by addition of a sodium hydroxide solution (50%). The basic liquor was then extracted 3 times with 15 L of dichloromethane, and the combined extracts were subjected to med vacuum distillation to yield crude RS-Nicotine product as a dark brown oil. The dark brown oil was high vacuum distilled twice to yield RS-Nicotine having a purity that meets the requirements of the USP purity test.

Composition Example 11—Composition for Use in Electronic Vaping Devices

Ingredient Amount (wt %) Synthetic RS-nicotine 0.3% Glycerin 99.7%

The R,S nicotine was produced by the method of Example 10. The composition of the R,S nicotine had an R isomer to S isomer ratio of 1:1 (i.e., the synthetic nicotine was a racemic mixture of R and S isomers). The synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt % or less. The synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.

Composition Example 12—Composition for Use in Electronic Vaping Devices

Ingredient Amount (wt %) S-nicotine (synthetic) 0.3 Glycerin 99.7

The S-nicotine was produced by resolution of RS nicotine to semi-pure or enantio-pure (i.e., 98% or greater) synthetic S-nicotine using (+)-0,0′-di-p-toluoyl-D-tartaric acid. The synthetic S-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt % or less. The synthetic S-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.

Composition Example 13—Composition for Use in Electronic Vaping Devices

Ingredient Amount (wt %) RS nicotine (synthetic) 0.6 Vegetable Glycerin 99.4

The R,S nicotine was produced by the method of Example 10. The composition of the R,S nicotine had an R isomer to S isomer ratio of 1:1 (i.e., the synthetic nicotine was a racemic mixture of R and S isomers). The synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt % or less. The synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.

Composition Example 14—Composition for Use in Electronic Vaping Devices

Ingredient Amount (wt %) RS-Nicotine (synthetic) 0.3 S-Nicotine (synthetic) 0.3 Glycerin (synthetic) 99.4

The R,S nicotine was produced by the method of Example 10. The composition of the R, S nicotine had an R isomer to S isomer ratio of 1:1. The S-nicotine was produced by resolution of R,S-nicotine to semi-pure or enantio-pure (i.e., 98% or greater) S-nicotine using (+)-O,O′-di-p-toluoyl-D-tartaric acid.

As listed here, the nicotine component of the composition includes a mixture (or blend) of racemic RS nicotine and pure S nicotine, both of which are synthetic. The composition of the R,S nicotine had an R isomer to S isomer ratio of 1:1 (i.e., the synthetic RS nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt % or less. The synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine. Similarly, the synthetic S-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt % or less. The synthetic S-nicotine component also does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.

Composition Example 15—Composition for Use in Electronic Vaping Devices

Ingredient Amount (wt %) RS-Nicotine (synthetic) 0.3 S-Nicotine (tobacco-derived) 0.3 Glycerin 99.4

The R,S nicotine was produced by the method of Example 10. The tobacco-derived S-nicotine is off-the-shelf nicotine, such as one of the (−)-Nicotine products available from Sigma-Aldrich Co., LLC.

As listed here, the nicotine component of the composition included a mixture (or blend) of racemic RS nicotine (which is synthetic) and S-nicotine derived from tobacco (naturally sourced). The synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt % or less. The synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine. The tobacco-derived nicotine component may contain the contaminants discussed above normally found in tobacco-derived nicotine, and may also contain those contaminants in the amounts described above.

Composition Example 16—Composition for Use in Electronic Vaping Devices

Ingredient Amount (wt %) RS-Nicotine (synthetic) 0.3 S-Nicotine (tobacco-derived) 0.3 Glycerin 49.4 Propylene Glycol 50.0

The R,S nicotine was produced by the method of Example 10. The tobacco-derived S-nicotine is off-the-shelf nicotine, such as one of the (−)-Nicotine products available from Sigma-Aldrich Co., LLC.

As listed here, the nicotine component of the composition included a mixture (or blend) of racemic RS nicotine (which is synthetic) and S nicotine derived from tobacco (naturally sourced). The synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt % or less. The synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine. The tobacco-derived nicotine component may contain the contaminants discussed above normally found in tobacco-derived nicotine, and may also contain those contaminants in the amounts described above.

Composition Example 17—Composition for Use in Electronic Vaping Devices

Ingredient Amount (wt %) RS-Nicotine (synthetic) 0.3 Glycerin 49.7 Propylene Glycol 50.0

The R,S nicotine was produced by the method of Example 10. The composition of the R,S nicotine had an R isomer to S isomer ratio of 1:1 (i.e., the synthetic nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of less than 1 wt %, or about 0.5 wt % or less. The synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.

Composition Example 18—Composition for Use in Electronic Vaping Devices

Ingredient Amount (wt %) RS-Nicotine (synthetic) 0.3 Glycerin 69.7 Propylene Glycol 30.0

The R,S nicotine was produced by the method of Example 10. The composition of the R,S nicotine had an R isomer to S isomer ratio of 1:1 (i.e., the synthetic nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt % or less. The synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine.

Composition Example 19—Composition for Use in Electronic Vaping Devices

Ingredient Amount (wt %) RS-Nicotine (synthetic) 0.3 Glycerin 69.7 Propylene Glycol 20.0 Flavoring 10.0

The R,S nicotine was produced by the method of Example 10. The composition of the R,S nicotine has an R isomer to S isomer ratio of 1:1 (i.e., the synthetic nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of less than 1 wt %, or about 0.5 wt % or less. The synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine. The flavoring was obtained from Capella Flavors, Inc. (San Marcos, Calif.).

Composition Example 20—Composition for Use in Electronic Vaping Devices

Ingredient Amount (wt %) S-Nicotine (synthetic) 0.5 Glycerin 59.5 Propylene Glycol 20.0 Flavoring 20.0

The synthetic S-nicotine was produced by resolution of RS nicotine to semi-pure or enantio-pure (i.e., 98% or greater) S-nicotine using (+)-O,O′-di-p-toluoyl-D-tartaric acid. The synthetic S-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of about 0.5 wt % or less. The synthetic S-nicotine component also does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine. The flavoring was obtained from Capella Flavors, Inc. (San Marcos, Calif.).

Device Example 1—Liquid Composition in an “Open Tank” or “Open System” Vaping Device

Ingredient Amount (wt/vol %) Racemic RS-Nicotine 0.3 (synthetic) Glycerin 79.7 Flavoring 20.0

The R,S nicotine was produced by the method of Example 10. The composition of the R,S nicotine has an R isomer to S isomer ratio of 1:1 (i.e., the synthetic nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of less than 1 wt %, or about 0.5 wt % or less. The synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine. The flavoring was obtained from Capella Flavors, Inc. (San Marcos, Calif.).

In an “open tank” or “open system” vaping device, the user may fill and/or refill the tank or cartridge designed to house the vaping liquid. Open tank or open system vaping devices are popular due to their high level of customizability. For instance, open tank or open system devices are not limited to the vaping liquids provided with the device, and instead can be customized by the addition of any suitable vaping liquid to the open cartridge of the system. In this example, the open tank or open system device was the product marketed as “Sub Tank” by Shenzhen Kanger Technology Co., Ltd. (Shenzhen, China).

Device Example 2—Liquid Composition in a “Closed Tank” or “Closed System” Vaping Device

Ingredient Amount (wt/vol %) Racemic RS-Nicotine (synthetic) 0.12-0.60 Flavoring 10-25 Glycerin, propylene glycol, remainder or mixture thereof

The R,S nicotine was produced by the method of Example 10. The composition of the R,S nicotine has an R isomer to S isomer ratio of 1:1 (i.e., the synthetic nicotine is a racemic mixture of R and S isomers). The synthetic RS-nicotine component may have an amount of synthetic contaminants or synthetic impurities (as those terms are defined above) of less than 1 wt %, or about 0.5 wt % or less. The synthetic RS-nicotine component does not include other contaminants, such as those normally associated with naturally sourced (or tobacco derived) nicotine. The flavoring was obtained from Capella Flavors, Inc. (San Marcos, Calif.).

Unlike the “open tank” or “open system” vaping device, in a “closed tank” or “closed system” vaping device, the vaping liquid is pre-charged into a closed container or cartridge mounted in the closed system device. This pre-charged cartridge is not fillable or refillable by the user of the device. Indeed, most “closed tank” or “closed system” vaping devices are designed as disposable after exhaustion of the vaping liquid in the pre-charged cartridge (e.g., e-cigarettes or so-called “cig-a-likes”).

Comparative Testing

A double blind study was conducted with several e-liquid manufacturers with over 250 people. Each person was given an electronic vaping device to vaporize and inhale a liquid nicotine composition. Each device contained one of two possible liquid nicotine compositions. The first composition included 0.3 wt % synthetic nicotine as a racemic mixture, and 99.7 wt % glycerin. The second composition (i.e., the comparative composition) included 0.3 wt % tobacco-derived nicotine commercially available from Alltech Associates Inc. (an affiliate of W.R. Grace & Co.), and 99.7 wt % glycerin. Thus, the only difference between the compositions was that the nicotine in the first composition was purely synthetic nicotine and the nicotine in the second composition was purely tobacco-derived nicotine. The users were not informed whether their electronic vaping devices contained the first composition or the second composition, and the testing was done according to typical sensory evaluation methods including a panel and questionnaire. In every single instance, the user stated that they preferred the sensation provided by the electronic vaping device comprising the first composition having the synthetic nicotine. In particular, the users expressed that, with respect to the composition comprising only synthetic nicotine, the flavors were much better, they could not taste or smell the nicotine, there was no tobacco after-taste, and that the nicotine impact was as strong as tobacco-derived nicotine.

From the manufacturer's perspective, the flavor blending was much easier because it was not necessary to mask the nicotine taste. Furthermore, the coils (or heating elements) in the vaping devices were found to burn clean all day. In contrast, the tobacco-derived nicotine compositions required large amounts of flavorants, which caused the devices to get dirty after a short period of time, necessitating cleaning the devices a number of times throughout the testing period.

In another study, 10 subjects were asked to “vape” three different nicotine compositions (each provided in two different concentrations of nicotine for a total of 6 compositions), and compare the head feel dynamics as well as the throat feel of each of the compositions. The first composition was a 0.3% synthetic S nicotine prepared according to the methods described herein; the second composition was a 0.3% tobacco-derived nicotine; the third composition was a 0.3% synthetic RS nicotine prepared by the methods described herein; the fourth composition was a 0.6% synthetic S nicotine prepared according to the methods described herein; the fifth composition was a 0.6% tobacco-derived nicotine; the third composition was a 0.6% synthetic RS nicotine prepared by the methods described herein. In rating the head feel dynamics and throat feel of the different compositions, the subjects used the following criteria:

Throat Feel Head Feel Dynamics 1 = none 1 = weak 2 = slight, not unpleasant 2 = noticeable 3 = moderate, noticeable 3 = moderate 4 = fairly strong, not pleasant 4 = fairly strong, pleasant 5 = strong, unpleasant 5 = very strong, pleasant Tables 1 and 2, below, list the results for the 0.3% and 0.6% compositions for each of the synthetic S, synthetic RS and tobacco derived nicotine.

TABLE 1 0.3% compositions 0.3% syn. S 0.3% syn. RS 0.3% tobacco 0.3% syn. S 0.3% syn. RS 0.3% tobacco Head Feel Head Feel Head Feel Subject # Throat Feel Throat Feel Throat Feel Dynamics Dynamics Dynamics 1 1 1 3 3 2 3 2 1 1 3 3 3 3 3 1 1 3 3 2 3 4 1 1 3 3 3 3 5 1 1 3 3 2 3 6 1 1 3 3 3 3 7 1 1 3 3 3 3 8 1 1 3 4 3 3 9 1 1 3 3 2 3 10  1 1 3 2 2 3 Average 1 1 3 3 2.5 3 Rating

TABLE 2 0.6% compositions 0.6% syn. S 0.6% syn. RS 0.6% tobacco 0.6% syn. S 0.6% syn. RS 0.6% tobacco Head Feel Head Feel Head Feel Subject # Throat Feel Throat Feel Throat Feel Dynamics Dynamics Dynamics 1 1 1 5 4 3 4 2 2 1 5 3 4 4 3 1 1 5 4 3 4 4 1 1 5 4 4 5 5 2 1 5 5 4 4 6 1 1 4 4 4 4 7 1 1 5 5 4 4 8 2 1 5 4 4 4 9 2 1 4 4 4 5 10  1 1 5 5 5 5 Average 1.4 1 4.8 4.2 3.9 4.3 Rating

As can be seen in Tables 1 and 2, above, at the 0.3% loading level, the synthetic “S” isomer had the same (within experimental error) “Head Feel Dynamics” as its Tobacco-derived counterpart; and the “RS” synthetic nicotine preparations had slightly less effect. The “Throat Feel” results show that the difference was detectable, and most likely predictable, where the synthetic nicotine preparations provided less of an effect, and therefore a more pleasant throat feel experience.

As also shown in Tables 1 and 2, the 0.6% loading level yielded more dramatic results. Similar to the less concentrated versions, but with a greater magnitude, the effect of the synthetic “S” isomer had the same (within experimental error) “Head Feel Dynamics” as its Tobacco-derived counterpart; and the “RS” synthetic nicotine preparations had slightly less effect. However, in stark contrast, he “Throat Feel” results for the 0.6% nicotine e-liquid preparations show that the difference was significant and readily detectable by all the subjects. For example, these results show that the synthetic nicotine e-liquid preparations provided a substantial and significantly different “Throat Feel”, while maintaining a similar “Head Feel Dynamic” than the tobacco-derived counterpart.

In an additional study of the differences between synthetic nicotine according to embodiments of the present invention and tobacco-derived nicotine, electrophysiology-based HTS assay was used to evaluate and compare the activity of different nicotine forms on two nicotinic ACh receptors (nAChRs), i.e., α7 and α4β2. The nicotinic forms subjected to this assay included an S nicotine available from Sigma-Aldrich Corporation, St. Louis, Mo., a synthetic RS racemic mixture of R and S isomers according to embodiments of the present invention, a synthetic S nicotine according to embodiments of the present invention, a synthetic RS mixture including 75% S and 25% R isomers according to embodiments of the present invention, a synthetic R nicotine according to embodiments of the present invention, a synthetic RS mixture including 25% S and 75% R isomers according to embodiments of the present invention, an S nicotine available from Alchem Laboratories Corporation, Alachua, Fla., and a reference nicotine available from Sigma-Aldrich. The results of the assay are provided in Tables 3 and 4 below, which show the obtained EC₅₀, IC₅₀, E_(max) and Hillslope values of receptor activation and inhibition.

TABLE 3 α4β2 nAChRs activation and inhibition Agonist Antagonist Effect Effect Emax, EC50, Hill- IC50, Hill- Composition % μM slope μM slope Sigma-Aldrich S nicotine 91 3.11 −0.84 0.01 0.94 Synthetic RS racemic nicotine 96 9.91 −0.77 0.03 1.27 Synthetic S nicotine 91 3.54 −0.88 0.01 0.93 Synthetic 75% S/25% R nicotine 99 5.15 −0.76 0.02 1.04 Synthetic R nicotine 28 10.79 −0.87 0.14 0.67 Synthetic 25% S/75% R nicotine 80 9.30 −0.90 0.04 1.11 Alchem S nicotine 103 3.71 −0.81 0.01 1.01 Ref. nicotine (Sigma-Aldrich) 100 4.13 −0.80 0.01 0.85

TABLE 4 α7 nAChRs activation and inhibition Agonist Antagonist Effect Effect Emax, EC50, Hill- IC50, Hill- Composition % μM slope μM slope Sigma-Aldrich S nicotine 104 1.20 −2.49 0.80 2.76 Synthetic RS racemic nicotine 108 2.07 −1.97 1.20 3.38 Synthetic S nicotine 102 1.07 −3.36 0.84 5.83 Synthetic 75% S/25% R nicotine 102 1.39 −2.64 0.99 5.16 Synthetic R nicotine 110 5.81 −2.37 4.07 2.55 Synthetic 25% S/75% R nicotine 105 2.69 −2.35 2.39 4.70 Alchem S nicotine 97 1.00 −3.15 0.73 3.06 Ref. nicotine (Sigma-Aldrich) 100 1.21 −2.23 0.92 10.02

As can be seen in the above Tables 3 and 4, the synthetic R nicotine according to embodiments of the present invention appears to be a full, weak agonist at human α7 nAChRs, but only a partial agonist at human α4β2 nAChRs, suggesting a selectivity of the nicotine isomers at different types of nAChRs, which is surprising and unexpected. For example, these results may suggest different neurophysiological responses to the R and S isomers of nicotine, and therefore different neurophysiological responses to various mixtures of the R and S isomers. These differences in the neurophysiological response may be responsible for the different sensory experiences reported in Tables 1 and 2 above, and these differences in membrane receptor binding properties of the R and S isomers may also affect psychoactive neuronal pathways as well as addictive responses.

As discussed above, vaping compositions according to embodiments of the present invention include a synthetic nicotine source that improves the vaping experience by the vaping consumer. For example, while vaping users can typically detect a foul taste in vaping liquids that use tobacco-derived nicotine, the same users typically cannot detect a similar foul taste in vaping liquids according to embodiments of the present invention using synthetic nicotine.

Additionally, while vaping liquids using tobacco-derived nicotine typically include large amounts of flavorants to mask the foul taste of the tobacco-derived nicotine, the vaping liquids according to embodiments of the present invention need not use so much flavorant. As discussed above, this reduction in the amount of flavorant can improve the lifespan of the vaping device in which the vaping liquid is used.

Moreover, vaping liquids using tobacco-derived nicotine typically have a harsh throat feel when vaporized by the vaping device, and generally have a strong “tobacco” odor. In contrast, the vaping liquids according to embodiments of the present invention using synthetic nicotine have a smoother throat feel, eliminating (or at least significantly reducing) the harsh feel associated with tobacco-derived nicotine. Additionally, the vaping liquids according to embodiments of the present invention include synthetic nicotine that is not derived from tobacco, and therefore exhibit significantly fewer “tobacco” odors.

While certain exemplary embodiments of the present disclosure have been illustrated and described, those of ordinary skill in the art will recognize that various changes and modifications can be made to the described embodiments without departing from the spirit and scope of the present invention, and equivalents thereof, as defined in the claims that follow this description. For example, although certain components may have been described in the singular, i.e., “a” flavorant, “a” solvent, and the like, one or more of these components in any combination can be used according to the present disclosure.

Also, although certain embodiments have been described as “comprising” or “including” the specified components, embodiments “consisting essentially of or” consisting of the listed components are also within the scope of this disclosure. For example, while embodiments of the present invention are described as including a nicotine source that comprises a synthetic nicotine, a nicotine source consisting essentially of or consisting of a synthetic nicotine is also within the scope of this disclosure. Accordingly, the nicotine source may consist essentially of the synthetic nicotine. In this context, “consisting essentially of” means that any additional components in the nicotine source will not materially affect the user experience in terms of taste or neurological effect. For example, a nicotine source consisting essentially of the synthetic nicotine may exclude any measurable or detectable amount of the contaminants or impurities described herein as normally associated with tobacco-derived nicotine.

As used herein, unless otherwise expressly specified, all numbers such as those expressing values, ranges, amounts or percentages may be read as if prefaced by the word “about,” even if the term does not expressly appear. Further, the word “about” is used as a term of approximation, and not as a term of degree, and reflects the penumbra of variation associated with measurement, significant figures, and interchangeability, all as understood by a person having ordinary skill in the art to which this disclosure pertains. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. Plural encompasses singular and vice versa. For example, while the present disclosure may describe “a” flavorant or “a” solvent, a mixture of such flavorants or solvents can be used. When ranges are given, any endpoints of those ranges and/or numbers within those ranges can be combined within the scope of the present disclosure. The terms “including” and like terms mean “including but not limited to,” unless specified to the contrary.

Notwithstanding that the numerical ranges and parameters set forth herein may be approximations, numerical values set forth in the Examples are reported as precisely as is practical. Any numerical value, however, inherently contains certain errors necessarily resulting from the standard variation found in their respective testing measurements. The word “comprising” and variations thereof as used in this description and in the claims do not limit the disclosure to exclude any variants or additions. 

What is claimed is:
 1. A composition suitable for use in a vaping device, the composition comprising: a nicotine product comprising a synthetic nicotine substantially free of one or more of nicotine-1′-N-oxide, nicotyrine, nornicotyrine, cotinine, 2′,3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, anabasine, and/or anatabine, and one or more pharmaceutically acceptable excipients, additives and/or solvents.
 2. The composition of claim 1, wherein the synthetic nicotine comprises pure S-nicotine, or a mixture of R-nicotine and S-nicotine.
 3. The composition of claim 2, wherein the mixture of R-nicotine and S-nicotine comprises a racemic mixture of R-nicotine and S-nicotine.
 4. The composition of claim 2, wherein the mixture of R-nicotine and S-nicotine comprises more R-nicotine than S-nicotine.
 5. The composition of claim 1, wherein the synthetic nicotine comprises greater than 5 wt % R-nicotine based on a total weight of the synthetic nicotine.
 6. The composition of claim 1, wherein the nicotine product further comprises a tobacco-derived nicotine.
 7. The composition of claim 6, wherein the nicotine product comprises about 10 wt % to about 90 wt % of the synthetic nicotine based on the total weight of the nicotine product, and the tobacco-derived nicotine accounts for the remainder of the nicotine product.
 8. The composition of claim 1, further comprising a flavorant.
 9. The composition of claim 1, wherein the composition is substantially free of flavorants.
 10. The composition of claim 1, wherein the nicotine product comprises 100 wt % of the synthetic nicotine.
 11. The composition of claim 1, wherein the one or more of nicotine-1′-N-oxide, nicotyrine, nornicotyrine, 2′,3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, cotinine, anabasine, and/or anatabine are present in the composition in a combined amount of less than 0.5 wt % based on the total weight of the composition.
 12. The composition of claim 1, wherein the one or more pharmaceutically acceptable excipients, additives and/or solvents comprises glycerin and/or propylene glycol.
 13. A vaping device, comprising: the composition of claim 1; and an atomizer for vaporizing the composition.
 14. The vaping device according to claim 13, wherein the synthetic nicotine comprises pure S-nicotine, or a mixture of R-nicotine and S-nicotine.
 15. The vaping device of claim 14, wherein the mixture of R-nicotine and S-nicotine comprises a racemic mixture of R-nicotine and S-nicotine.
 16. The vaping device of claim 14, wherein the mixture of R-nicotine and S-nicotine comprises more R-nicotine than S-nicotine.
 17. The vaping device of claim 13, wherein the synthetic nicotine comprises greater than 5 wt % R-nicotine based on a total weight of the synthetic nicotine.
 18. The vaping device of claim 13, wherein the nicotine product further comprises a tobacco-derived nicotine.
 19. The vaping device of claim 13, wherein the nicotine product comprises 100 wt % of the synthetic nicotine.
 20. The vaping device of claim 13, wherein the one or more of nicotine-1′-N-oxide, nicotyrine, nornicotyrine, 2′,3-bipyridyl, anabasine, N-methyl anatabine, N-methyl anabasine, cotinine, anabasine, and/or anatabine are present in the composition in a combined amount of less than 0.5 wt % based on the total weight of the composition. 